Cerebral tuberculosis in a patient with systemic lupus erythematosus following cyclophosphamide treatment: a case report.

Central nervous system (CNS) tuberculosis (TB) is a rare but catastrophic event in patients with systemic lupus erythematosus (SLE). Here we report a case of cerebral TB in a patient with lupus myocarditis and nephritis, following cyclophosphamide immunosuppression. To our knowledge this is the first reported case of cerebral TB in SLE in a non-endemic country. A 31-year-old female with SLE and a history of regular travel to Kenya presented to our centre with clinical features of acute heart failure. She was diagnosed with severe lupus myocarditis, and a renal biopsy also confirmed lupus nephritis. Prior to admission, she had also had a cough, fever and weight loss and was under investigation for suspected TB infection. She was treated with ivabradine, beta-blockers and diuretics together with methylprednisolone and cyclophosphamide immunosuppression. Subsequent sputum cultures confirmed TB and she was commenced on triple therapy. Despite this, she developed confusion, dizziness, blurred vision and fluctuating consciousness. Magnetic resonance imaging (MRI) and lumbar puncture revealed CNS TB infection resulting in meningitis. This was later complicated by obstructive hydrocephalus due to TB abscesses. A ventriculoperitoneal (VP) shunt was inserted and TB medications were given intravenously (IV) with dexamethasone. Following a prolonged hospital admission, the patient eventually recovered and rituximab treatment was used to control her SLE. TB infection has been associated with SLE flares. It is likely in this case that TB exacerbated a lupus flare and subsequent immunosuppression resulted in mycobacterial dissemination to the CNS. Systemic and CNS features of TB and SLE are difficult to distinguish and their contemporaneous management represents a diagnostic and therapeutic challenge.

Burden of illness in systemic lupus erythematosus: results from a UK patient and carer online survey.

Objective The objective of this study was to assess the impact of systemic lupus erythematosus (SLE) on patients and carers. Methods Adults with SLE and carers of SLE patients completed a UK-specific online survey covering many aspects of the disease. Surveys were developed in collaboration with an NHS lupus unit and a lupus patient organization. Results A total of 121 patients and 31 carers completed the surveys. Of the 70% of patients initially misdiagnosed with another condition, 59% received treatment for the misdiagnosis. Fatigue was the most debilitating symptom, experienced daily by 79% of patients. The proportion of patients not reporting flares to healthcare providers varied with flare severity: mild flares (43%), moderate flares (15%) and severe flares (5%). Most patients (89%) reported reduced ability to socialize, and 76% had changed employment; of these, 52% stopped working completely. Over one-half (52%) of carers in paid employment missed time from work, and 55% of carers reported a worsened financial status. Most carers (87%) experienced interference with social activities. Conclusion SLE is commonly misdiagnosed and has a considerable impact on the physical, social and financial status of patients and carers. Increased awareness of the disease among healthcare providers and employers of patients and their carers is needed.

Increased risk of vascular complications in Takayasu's arteritis patients with positive lupus anticoagulant.

OBJECTIVES: Previous studies have shown antiphospholipid antibodies (aPL) to be prevalent in primary systemic vasculitides; however, the possible clinical impact of aPL positivity in such patients has not been explored in depth. The aims of this study were to determine the prevalence of aPL in patients with Takayasu's arteritis (TA) and to ascertain whether aPL positivity was predictive of a worse clinical outcome in TA. METHOD: Clinical data were collected retrospectively on 22 TA patients over an 11-year period. Data collected included the presence of lupus anticoagulant (LA) and immunoglobulin (Ig)G and IgM anticardiolipin antibody (aCL) titres. Adverse clinical outcomes included cerebrovascular accident (CVA), transient ischaemic attack (TIA), loss of vision, vascular lesions (carotid, femoral, renal, coronary, or other vessels) requiring stenting, angioplasty, or other surgical intervention, aortic valve replacement, end-stage renal failure or death. RESULTS: Persistently positive aPL or a concurrent diagnosis of antiphospholipid syndrome (APS) was found in 45% (n = 10) of TA patients while 55% (n = 12) had TA alone. LA was present in a significant proportion of TA patients with aPL (p = 0.002). Vascular complications occurred in 70% (n = 7) of TA patients with aPL and in 25% (n = 3) of TA patients without aPL (p = 0.035). LA was associated with a higher prevalence of vascular complications. CONCLUSIONS: Persistently positive aPL are present in a significant proportion of TA patients. This study shows that vascular complications and need for intervention are more prevalent in TA patients with aPL, particularly those with LA. Prospective studies are needed to determine the long term prognosis in such patients.

Rituximab in the treatment of resistant lupus nephritis: therapy failure in rapidly progressive crescentic lupus nephritis.

OBJECTIVE: The objective of this paper is to report the clinical outcome of B cell depletion therapy in 18 patients with refractory lupus nephritis (LN). METHODS: Eighteen patients received rituximab on an open-label basis with prospective evaluations. All patients had renal disease refractory to conventional immunosuppressive therapy, including intravenous cyclophosphamide (CyC). All patients fulfilled the revised ACR classification criteria for SLE. Rituximab was given as 2 × 1 g infusions with 500 mg iv CyC and 500 mg iv methylprednisolone, two weeks apart. Complete remission (CR) of nephritis at six months was defined as normal serum creatinine and serum albumin levels, inactive urine sediment, and proteinuria < 0.5 g/day; partial remission (PR) was defined as a ≥50% improvement in all renal parameters that were abnormal at baseline. Clinical response was assessed by the British Isles Lupus Assessment Group (BILAG) score pre- and post-rituximab treatment, and efficacy was recorded by extent and duration of B lymphocyte depletion (normal range 0.100-0.500 × 10(9)/l). Follow-up data were collected at six months, one year post-treatment and at the most recent clinic visit. RESULTS: At six months, 11/18 patients reached renal CR and two of 18 PR. The mean global BILAG scores for responders decreased from 15 (SD 10) to 5 (SD 3), and a total of ten A scores disappeared. Five patients failed to show complete or partial renal response despite peripheral B lymphocyte count depletion, and progressed to end-stage renal failure (ESRF) and dialysis. Four of these patients had severe proliferative, crescentic nephritis, of whom three had Class IV-G, one Class III and one late membranous glomerulonephritis. One patient died six years after rituximab therapy from overwhelming sepsis while on long-term haemodialysis. CONCLUSION: Rituximab therapy achieved a response in 13/18 patients with refractory LN. However, in patients with rapidly progressive crescentic LN, when there is already evidence of significant renal impairment, rituximab therapy may not prevent progression to ESRF and dialysis. Our data also suggest that severe Class IV-G LN may be associated with a poor response to therapy.

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE.

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Correlation of 24-hour urinary protein quantification with spot urine protein:creatinine ratio in lupus nephritis.

OBJECTIVES: Twenty-four hour urine collection has been the foundation for monitoring patients with lupus nephritis. However, the use of protein to creatinine ratios in spot urine samples is now widely used. We aimed to evaluate the validity of this method cross-sectionally and longitudinally. METHODS: A cross-sectional retrospective study was conducted. Records of 486 lupus nephritis patients were searched for paired results of 24-h quantification of urinary protein and a random spot urine protein to creatinine ratio and were examined over a three-year period. RESULTS AND CONCLUSIONS: Ninety-five lupus nephritis patients had paired results and were included in the final analysis, male/female 14/81, mean age 36.5 years. Over a three-year period there were a total of 137 samples from 95 patients. For the entire dataset, there was a significant correlation between protein:creatinine ratio and 24-h urine collection protein (mg), Spearman Rho correlation coefficient was 0.869, p < 0.0001 with (R (2 )= 0.504). There was also a strong correlation for longitudinal data, n = 14 at two-years Rho 0.910, p < 0.0001 with (R (2 )= 0.878), n = 8 at three-years Rho 0.909, p < 0.0001 and (R (2 )= 0.73). We have shown for the first time in a UK population of lupus nephritis patients, well trained in producing 24-h collection, that the spot protein:creatinine ratio correlates well with 24-h urinary total protein excretion. Having a simple, reliable, reproducible and cost-effective test such as the spot urine protein:creatinine ratio is therefore a valuable tool with which to monitor disease progression.

Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) may require prolonged periods of corticosteroid therapy which lead to excessive weight gain and increased cardiovascular risk. OBJECTIVE: To assess the utility of a low glycaemic index diet in patients with corticosteroid dependent SLE in achieving weight loss and improving glycaemic control. DESIGN: A total of 23 women were enrolled in a 6 week study. All had mild, stable SLE, were receiving corticosteroids and had a body mass index > 25 kg/m(2). Subjects were randomly assigned to a low glycaemic index (Low GI) diet or a calorie restricted (Low Cal) diet. The primary end point was weight loss. Secondary end points included tolerability of diet, bio-markers of cardiovascular risk, disease activity, fatigue and sleep quality. RESULTS: Weight loss in both treatment groups was significant (mean ± SD: Low GI diet 3.9 ± 0.9 kg; Low Cal diet 2.4 ± 2.2 kg, p < 0.01 from baseline in each group). There were also significant improvements in waist and hip measurements. However, the difference in weight loss and waist and hip measurements between the two diet groups was not statistically significant. There was a statistically significant reduction in Fatigue Severity Scale in both diet groups, (p < 0.03). Both Low GI and Low Cal diets were well tolerated, resulting in no serious adverse effects or increase in disease activity. CONCLUSION: Significant weight loss is achievable over 6 weeks in a diet-specific trial in subjects with stable SLE, who are on low dose prednisolone. Both diets were equally tolerable, and did not cause flares in disease activity. Our results suggest that dietary manipulation may significantly improve fatigue in subjects with SLE.

An assessment of disease flare in patients with systemic lupus erythematosus: a comparison of BILAG 2004 and the flare version of SELENA.

AIMS: To compare the British Isles Lupus Assessment Group (BILAG) 2004, the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and physician's global assessment (PGA) in assessing flares of disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Sixteen patients with active SLE were assessed by a panel of 16 rheumatologists. The order in which the patients were seen was randomised using a 4×4 Latin square design. Each patient's flare status was determined at each assessment using the BILAG 2004 activity index; the SFI and a PGA. A group of five specialists designated each patient into severe, moderate, mild or no flare categories. RESULTS: The rate of complete agreement (95% CI) of the four individual examining physicians for any flare versus no flare was 81% (55% to 94%), 75% (49% to 90%) and 75% (49% to 90%) for the BILAG 2004 index, SELENA flare instrument and PGA, respectively. The overall agreement between flare defined by BILAG 2004 and the SFI was 81% and when type of flare was considered was 52%. Intraclass correlation coefficients (95% CI), as a measure of internal reliability, were 0.54 (0.32 to 0.78) for BILAG 2004 flare compared with 0.21 (0.08 to 0.48) for SELENA flare and 0.18 (0.06 to 0.45) for PGA. Severe flare was associated with good agreement between the indices but mild/moderate flare was much less consistent. CONCLUSIONS: The assessment of flare in patients with SLE is challenging. No flare and severe flare are identifiable but further work is needed to optimise the accurate 'capture' of mild and moderate flares.

The development of a simple questionnaire to screen patients with SLE for the presence of neuropsychiatric symptoms in routine clinical practice.

AIM: The creation of a physician-administered questionnaire to screen patients with Systemic Lupus Erythematosus (SLE) for the presence of symptoms suggestive of neuropsychiatric involvement (NPSLE). METHODS: The development of the questionnaire followed three phases. First, a list of manifestations was prepared based on the ACR case definitions for NPSLE. A first questionnaire was constructed including 119 items. To reduce their number, a Delphi analysis was carried out and a second questionnaire with 62 questions was developed. This questionnaire was administered to 139 patients with SLE (58 with NPSLE: 29 active, 29 inactive; and 81 without NPSLE: 39 active, 42 inactive). Questions relevant to the screening of patients were selected on the basis of the receiver operating characteristic (ROC) curve analysis. RESULTS: Twenty-seven questions concerning central nervous system and psychiatric manifestations were found to be relevant; the remaining could be eliminated without significantly affecting AUC. The area under the ROC curve (AUC) was 0.69 (95% CI 0.61-0.78). A score above 17 was considered as suggestive of the presence of NPSLE with a sensitivity of 92.9% (95% CI 85.1-97.3 %) and specificity of 25.4% (95% CI 14.7-39.00 %). CONCLUSIONS: This questionnaire could represent a 'core set' of questions that could help in clinical practice to identify patients with neuropsychiatric symptoms requiring further evaluation.

The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate abatacept therapy in patients with non-life-threatening systemic lupus erythematosus (SLE) and polyarthritis, discoid lesions, or pleuritis and/or pericarditis. METHODS: In a 12-month, multicenter, exploratory, phase IIb randomized, double-blind, placebo-controlled trial, SLE patients with polyarthritis, discoid lesions, or pleuritis and/or pericarditis were randomized at a ratio of 2:1 to receive abatacept (∼10 mg/kg of body weight) or placebo. Prednisone (30 mg/day or equivalent) was given for 1 month, and then the dosage was tapered. The primary end point was the proportion of patients with new flare (adjudicated) according to a score of A/B on the British Isles Lupus Assessment Group (BILAG) index after the start of the steroid taper. RESULTS: A total of 118 patients were randomized to receive abatacept and 57 to receive placebo. The baseline characteristics were similar in the 2 groups. The proportion of new BILAG A/B flares over 12 months was 79.7% (95% confidence interval [95% CI] 72.4, 86.9) in the abatacept group and 82.5% (95% CI 72.6, 92.3) in the placebo group (treatment difference -3.5 [95% CI -15.3, 8.3]). Other prespecified flare end points were not met. In post hoc analyses, the proportions of abatacept-treated and placebo-treated patients with a BILAG A flare were 40.7% (95% CI 31.8, 49.5) versus 54.4% (95% CI 41.5, 67.3), and the proportions with physician-assessed flare were 63.6% (95% CI 54.9, 72.2) and 82.5% (95% CI 72.6, 92.3), respectively; treatment differences were greatest in the polyarthritis group. Prespecified exploratory patient-reported outcomes (Short Form 36 health survey, sleep problems, fatigue) demonstrated a treatment effect with abatacept. The frequency of adverse events (AEs) was comparable in the abatacept and placebo groups (90.9% versus 91.5%), but serious AEs (SAEs) were higher in the abatacept group (19.8 versus 6.8%). Most SAEs were single, disease-related events occurring during the first 6 months of the study (including the steroid taper period). CONCLUSION: Although the primary/secondary end points were not met in this study, improvements in certain exploratory measures suggest some abatacept efficacy in patients with non-life-threatening manifestations of SLE. The increased rate of SAEs requires further assessment.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.

OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. CONCLUSION: The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.

Mathematical analysis of antigen selection in somatically mutated immunoglobulin genes associated with autoimmunity.

Affinity maturation is a process by which low-affinity antibodies are transformed into highly specific antibodies in germinal centres. This process occurs by hypermutation of immunoglobulin heavy chain variable (IgH V) region genes followed by selection for high-affinity variants. It has been proposed that statistical tests can identify affinity maturation and antigen selection by analysing the frequency of replacement and silent mutations in the complementarity determining regions (CDRs) that contact antigen and the framework regions (FRs) that encode structural integrity. In this study three different methods that have been proposed for detecting selection: the binomial test, the multinomial test and the focused binomial test, have been assessed for their reliability and ability to detect selection in human IgH V genes. We observe first that no statistical test is able to identify selection in the CDR antigen-binding sites, second that tests can reliably detect selection in the FR and third that antibodies from nasal biopsies from patients with Wegener's granulomatosis and pathogenic antibodies from systemic lupus erythematosus do not appear to be as stringently selected for structural integrity as other groups of functional sequences.

Clinical guidelines for the management of acute viral infections in patients with systemic lupus erythematosus.

In recent decades, many research groups have focused on the role of viral infections in the etiopathogenesis of systemic lupus erythematosus (SLE), the so-called "viral hypothesis". The main candidates are herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), which have a high seroprevalence in the general population. However, a viral causal agent of SLE has not yet been discovered, although many interesting clinical findings on the complex interactions between viruses and SLE have been made. This review analyzes 88 cases of acute viral infections in adult patients with SLE and identifies situations in which viral infections influenced the diagnosis, prognosis or treatment of SLE. We also propose clinical guidelines for the management of these infections in patients with SLE.

BILAG-2004 index captures systemic lupus erythematosus disease activity better than SLEDAI-2000.

OBJECTIVE: To assess the reliability of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000 index in routine practice and its ability to capture disease activity as compared with the British Isles Lupus Assessment Group (BILAG)-2004 index. METHODS: Patients with systemic lupus erythematosus from 11 centres were assessed separately by two raters in routine practice. Disease activity was assessed using the BILAG-2004 and SLEDAI-2000 indices. The level of agreement for items was used to assess the reliability of SLEDAI-2000. The ability to detect disease activity was assessed by determining the number of patients with a high activity on BILAG-2004 (overall score A or B) but low SLEDAI-2000 score (<6) and number of patients with low activity on BILAG-2004 (overall score C, D or E) but high SLEDAI-2000 score (>or=6). Treatment of these patients was analysed, and the increase in treatment was used as the gold standard for active disease. RESULTS: 93 patients (90.3% women, 69.9% Caucasian) were studied: mean age was 43.8 years, mean disease duration 10 years. There were 43 patients (46.2%) with a difference in SLEDAI-2000 score between the two raters and this difference was >or=4 in 19 patients (20.4%). Agreement for each of the items in SLEDAI-2000 was between 81.7 and 100%. 35 patients (37.6%) had high activity on BILAG-2004 but a low SLEDAI-2000 score, of which 48.6% had treatment increased. There were only five patients (5.4%) with low activity on BILAG-2004 but a high SLEDAI-2000 score. CONCLUSIONS: SLEDAI-2000 is a reliable index to assess systemic lupus erythematosus disease activity but it is less able than the BILAG-2004 index to detect active disease requiring increased treatment.

Ankle-brachial pressure index: a simple tool for assessing cardiovascular risk in patients with systemic vasculitis.

OBJECTIVE: Cardiovascular disease may be increased in patients with systemic vasculitides (SV). The Ankle-Brachial Pressure Index (ABPI) is a non-invasive tool for the assessment of cardiovascular risk (CV). Our aim was to determine the prevalence of an abnormal ABPI in patients with SV and healthy controls and to correlate with clinical and serological parameters. METHODS: We studied 54 consecutive vasculitis patients (20 males) attending the vasculitis clinic and 49 healthy subjects. Patients were classified according to the ACR 1990 criteria and the Chapel Hill Consensus definitions. There were 18 patients with Wegener's granulomatosis, eight with Behcet's disease, seven with Churg-Strauss Syndrome, three with Henoch-Schonlein purpura, three with polyarteritis nodosa, three with Takayasu's disease, three with p-ANCA associated vasculitis, three with urticarial vasculitis, two with cutaneous leucocytoclastic angiitis, one with microscopic polyangiitis, one with primary central nervous system angiitis, one giant cell arteritis and one with cutaneous vasculitis secondary to Sjogren's syndrome. Traditional risk factors as well as glucose, lipid profile, CRP, hsCRP, ANCA and aPL were assessed. ABPI was measured according to a consensus statement on the methodology. RESULTS: The ABPI was abnormal in 11/54 (20.4%) of SV patients and 2/49 (4%) of the control group (chi(2) with Yates correction = 4.8, P

Low-dose intra-venous cyclophosphamide therapy in a patient with neurological complications of Behçet's disease.

Behçet's disease (BD) is a chronic relapsing-remitting inflammatory disorder of unknown origin, affecting multiple organs. Neurological involvement is one of the most devastating manifestations of BD and may be fatal. We report a 36-year-old woman with neuro-Behçet who was treated with low-dose pulse cyclophosphamide (St. Thomas' protocol) and methylprednisolone, with almost complete clinical remission.

[Orthopedic manifestations of the antiphospholipid syndrome]. / Manifestations osseuses du syndrome des antiphospholipides.

PURPOSE: The antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis, and pregnancy morbidity in association with antiphospholipid antibodies. Since its classical description 22 years ago, the clinical spectrum of APS has embraced the realms of obstetrics, nephrology, cardiology, neurology, gastroenterology, angiology and now, possibly orthopaedics. This is not surprising given that this disease can affect virtually any organ system and blood vessel of any size and nature. Just as venous thrombosis may affect limbs and internal organs, arterial thrombosis has been shown to affect organs such as the brain, eye, heart, kidney, liver and may also involve the skeleton. CURRENT KNOWLEDGE AND KEY POINTS: In this review, we describe the orthopedic aspects of APS recently reported, bone metatarsal fractures, osteonecrosis and more exceptional complications, ie algodystrophy and bone marrow necrosis. We briefly discuss postulated pathogenesis and possible implications of anticoagulation. FUTURE PROSPECTS AND PROJECTS: This data need further confirmation. They may suggest complementary physiopathologic and therapeutic implications.